The present invention relates to novel therapeutic methods and pharmaceutical compositions for treating warts. More particularly, the present invention relates to novel therapeutic methods and pharmaceutical compositions for treating ailments caused by human papilloma viruses.
Human papilloma virus (HPV) infections are common infections of the outer layer of the skin, which affect most persons sometime during their lifetime. To date, over seventy distinct types of HPVs have been already identified. These viruses target the squamous epithelia of the skin and mucosal membranes. Based on this trophism, the different types of HPV have been subdivided into two large categories: cutaneous and mucosal. A third category is sometimes used to designate types of HPV specifically found in people with epidermodysplasia verruciformis (EV).
HPV infections typically emerge as skin warts. However, by being spread by auto-innoculation, warts may also occur at any other location in the body. Subjects afflicted with warts may in some cases experience complete regression after several months with or without treatment with recurrence at the same or at different locations.
Skin warts include, for example, common warts (e.g., verruca vulgaris, plantar, palmar and periungal); planar warts (verruca plana); mosaic warts; genital and venereal warts (e.g., condylomata acuminata); butcher's warts; malignant epidermodyspasia verruciformis; advanced intraepithelial dysplasia, mepidermodysplasia verruciformis; cutnaeous warts in immunosuppressed patients; laryngeal papillomas; and oral papilloma. However, clinical manifestations sometimes further include serious infections of the genital mucous membranes, (e.g., advanced intraepithelial dysplasia), which may progress to cervical cancer.
Skin warts resulting from HPVs are unsightly and irritating, and although the majority of such infections are benign and self-limited, there are subtypes of papilloma virus that are considered pre-malignant in certain clinical settings. Therefore, the removal of emerged skin warts is highly recommended.
Throughout the years a number of therapies have been developed for treating these coetaneous infections. However, most of the presently known methods of treating warts are painful, expensive, requiring long treatment periods and/or are ineffective. Most of these methods are initially successful but involve a longer-term treatment failure, exhibited by recurrence, as well as side effects [see, for example, Goldfarb et al., Dermatol Clin, 1991; 9(2):287-96; Hettich, Dermatologica, 1984; 168 Supple 1:36-42; Bunney, M. H., Viral warts: their biology and treatment. New York, N.Y.: Oxford University Press Inc., 1982; Belisario, Australas J Dermatol, 1951; 1:20-30; and Beutner et al. Lancet, 1989; 1831-834].
The presently used methods of treating HPV infections typically include the use of locally destructive chemicals or agents, such as salicylic acid, lactic acid, trichloracetic acid, dichloroacetic acid, nitric acid and glacial acetic acid; surgically destructive methods such as excision, electrocautery, electrodesiccation, curettage, blunt dissection and laser vaporization or coagulation; blister-producing methods such as liquid nitrogen cryotherapy, carbon dioxide cryotherapy and cantharidin; cellular inhibition, which uses agents such as podophyllin and podophyllotoxin, 5-fluorouracil, bleomycin, colchicine, interferon local injections and radiation; altering the cutaneous environment, which includes agents or techniques such as retinoids, formalin, glutaraldehyde, aluminum chloride and heat therapy; and immune stimulation methods of treatment, which include dinitrochlorobenzene (DNCB), imiquimod (also known by the trade name Aldara™), interferon systemic injections and vaccination, either autologous or intralesional.
Hence, the presently most common methods of warts treatment can be divided into chemical, surgical and physical methods. The physical methods typically include destruction of the infected keratinocytes by cooling (e.g., liquid nitrogen) or heating (e.g., electrocautery, CO2 laser), and often lead to injury of surrounding tissues, secondary infections and other undesired consequences.
Surgical treatments are typically associated with discomfort, prolonged healing and the formation of scars and/or keloids, is addition to an inherent risk.
The chemical methods commonly use locally destructive chemicals and typically include caustic chemicals that act through nonspecific destructive mechanisms to cause cell death, killing the infected keratinocytes. The keratinocytes are subsequently desquamated from the skin surface. This non-specific form of destructive therapy often causes side effects such as pain, secondary infection, permanent scarring and is oftentimes associated with recurrence of disease.
The chemical methods typically involve topical application of the chemical agents as solutions, tinctures, creams, ointments, patches, etc. One of the presently most used chemical agents for treating warts is salicylic acid, which is typically administered as a patch or a gel. A typical salicylic acid patch contains an amount of salicylic acid in a sticky base or a rubber base. However, the use of salicylic acid in the treatment of HPV requires repeated administration of the composition for a prolonged period of about 4-6 weeks, and is oftentimes unsuccessful.
Hence, most of the currently available methods focus on the destruction of visible lesions rather than the underlying cause of disease, namely the HPV. For example, removal of warts with destructive chemical agents or with physical ablative means do not affect viral particles that may be lurking in normal-appearing areas surrounding the wart. This is one of the reasons of the high rate of disease recurrence.
The inefficiency of the presently known methods of treating warts have been widely studied and reported in the art. Thus, it was found that using a liquid nitrogen, initial cure is seen in 52-83% of patients [Berth-Jones and Hutchinson, Br J Dermatol, 1992; 127(3):262-5; Erkens et al., J. A., Ned Tijdschr Geneeskd, 1991; 135(5):171-4]; Keefe and Dick. Clin Exp Dermatol, 1990; 15(4):260-3], however, only 57% of the patients remain clear of warts after a median of 19 months [Keefe and Dick. Clin Exp Dermatol, 1990; 15(4):260-3].
When using a histofreezer technique the success rate falls to 28% [Erkens et al., J. A., Ned Tijdschr Geneeskd, 1991; 135(5):171-4] and is comparable with placebo or the success rates achieved through direct in hypnotic suggestion (27-55%) [Ewin, D. M., Am J Clin Hypn, 1992; 35(1):1-10]. Recently, however, individual byproanalytic techniques were shown to cure 80% of patients who have failed hypnosis [Robson et al., J Am Acad Dermatol, 2000; 43(2 Pt 1):275-80].
Since 1970 intralesional bleomycine therapy success rate has remained in the 70% range [see, for example, Sobh et al., Acta Derm Venereol Stockh, 1991; 71(1):63-6; Shelley and Shelley, Arch Dermatol, 1991; 127(2):234-6; Hayes and O'Keefe, J Am Acad Dermatol, 1986; 15:1002-1006; Mishima and Matunaka, Acta Derm Venereol (Stockh), 1971; 52:211-215; and Bennett and Reich, Ann Intern Med, 1979; 90:945-948]. However, it was found that not all warts are suitable for intralesional bleomycine, the treatment exhibit significant systemic drug exposure and significant local adverse and side effects. In addition, multiple treatments are required to achieve substantial success.
Summarizing various published reports indicates that topical standard salicylic acid treatment results, at best, in 40% cure rate after 4 weeks compared to 8% cure in the placebo group. Treatment with trichloro acetic acid typically results in 64-81% cure rate, whereby treatment with 5-fluorouracil typically results in even lower cure rates ranging from 10 to 50%. Carbon dioxide laser evaporation for recalcitrant warts results in 31-86% cure rate. This treatment, however, may result in significant morbidity.
Using superpulsed mode to overcome these limitations was found to convey only a slight advantage. Comparable results were obtained with infrared coagulation. Early studies with pulsed dye lasers showed promising results, which have not been confirmed yet by later studies.
Since recalcitrant and recurrent warts are more common in patients with a cell-mediated immune deficiency state, it is suggested that spontaneous regression or successful treatment depend on either naturally or iatrogenically related stimulation of immunity [Robson et al. J Am Acad Dermatol, 2000; 43(2 Pt 1):275-80]. Thus, several systemic and topical immunotherapies for warts have been reported, including squalic acid dibutylester, levamizole, and interferons beta and gamma. The efficacy of these therapies, however, was not definite.
The presently known methods for treating warts therefore suffer major disadvantages, in terms of both efficacy and adverse side effects associated therewith.
There is thus a widely recognized need for, and it would be highly advantageous to have novel methods of treating warts, devoid of the above limitations.
Various tellurium compounds have been described in the art as having immunomodulating properties. These compounds are taught, for example, in U.S. Pat. Nos. 4,752,614; 4,761,490; 4,764,461 and 4,929,739, and in a recently filed U.S. Provisional Patent Application No. 60/610,660, which are all incorporated by reference as if fully set forth herein. U.S. Pat. No. 4,752,614, which is also incorporated by reference as if fully set forth herein, teaches the use of certain tellurium compounds in the treatment of certain tumors, autoimmune diseases, immune diseases and infectious diseases. An anti-viral activity of these compounds was demonstrated in this patent in plants and animals, whereby the virus that is exemplified is West Nile Virus, which affects the central nervous system.
The use of tellurium compounds to treat HPV and hence warts has never been suggested nor practiced hitherto.